(8 beta)-6-methylergoline amide derivatives as serotonin antagonists: N1-substituent effects on vascular 5HT2 receptor activity.
A series of (8 beta)-6-methylergoline amide derivatives was synthesized with various alkyl substituents in the N1-position in order to evaluate their effectiveness in blocking vascular 5HT2 receptors. The influence of both the N1 substituent and amide derivative proved to be of great importance on binding affinities to vascular 5HT2 receptors. Within each series of amides, however, maximum affinity was achieved with an N1-isopropyl substituent (14, 18, 26, 38, and 41; all with 2.7-50 times greater affinity than their N1-H analogues), with the exception of two cases (22 and 37) in the cyclohexylamide derivatives wherein N1-methyl equalled the isopropyl in potency. Other than these exceptions, affinities followed the pattern of H less than Me less than Et less than iPr, with potencies falling off with larger alkyl substituents.
Misner
J W
JW
Lilly Research Laboratories, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, Indiana 46285.
Garbrecht
W L
WL
Marzoni
G
G
Whitten
K R
KR
Cohen
M L
ML
D000577:Amides; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004873:Ergolines / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
D000577:Amides; D004873:Ergolines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists